PHARMACOLOGIC MANAGEMENT FOR INFLAMMATORY BOWEL DISEASE: ULCERATIVE COLITIS & CROHN S DISEASE

Transcription

1 PHARMACOLOGIC MANAGEMENT FOR INFLAMMATORY BOWEL DISEASE: ULCERATIVE COLITIS & CROHN S DISEASE Joseph Reilly, B.S., Pharm.D. Residency Program Director / Clinical Specialist AtlantiCare Regional Medical Center

2 OBJECTIVES Differentiate between the various oral mesalamine preparations for Ulcerative Colitis & Crohn's Disease Describe the pharmacologic actions of anti TNF monoclonal antibody therapies for Inflammatory Bowel Disease

3 We ve come a long way IBD is recognized Crohn s & UC described Prednisone Sulfasalazine Mesalamine Azathioprine Methotrexate Remicade Humira Cimzia Tysabri

4 Goals of Therapy in the Inflammatory Bowel Diseases Symptom Improvement Improve the Future Reduce Hospitalization Reduce need for surgery Reduce social & occupational burden Mucosal Healing Targeted Therapy Against Inflammation in IBD Improve Safety and Tolerability of Medications

5 Differences Between Crohn's Disease and UC Location Distribution Depth of inflammation Complications Crohn's Disease Affect any part of the GIT, from mouth to anus Patchy areas of inflammation Skip lesions Deep into tissues Strictures, Obstruction Abscess, Fistula Ulcerative Colitis Restricted to colon & rectum Continuous area of inflammation Shallow, mucosal Toxic megacolon Colon cancer

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7 Ulcerative colitis Crohn's disease

8 CANCER RISK AND IBD No increased risk with proctitis 2 Cumulative Ca rate (3 centers) for UC = 20 years, 30 years Conclusion: Similar risk of CD as with UC 3,4 Colon Cancer Prevention in UC 81% reduction with regular 5 ASA use. 6 2 Ekbom A, Helmick C, Zack M, et al. N Engl J Med 1990; 323: Edwards FC, Truelove SC. Gut 1964; 5: Gyde SN, Prior P, Allan RN, et al. Gut 1988;29: Pardi S. Gastroenterology 2003; 124: Eaden JA, Abrams K, Ekborn A, et al. Aliment Parmacol Ther 2000; 14:

9 Danese et al, EXTRAINTESTINAL MANIFESTATIONS

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11 DIAGNOSIS

12 Treatment of IBD 1. 5-amino salicylic acid compounds (5-ASA) - Mesalamine based oral or topical 2. Glucocorticoids 3. Immunomodulators 4. Biological therapy (TNF-α inhibitors) 5. Surgery

13 5-amino salicylic acid compounds (5-ASA) Aminosalicylates Topical anti-inflammatory drugs, 5-ASA has anti-inflammatory action due to: - inhibition of prostaglandins and leukotrienes - decrease neutrophil chemotaxis - antioxidant activity (scavenging free radical production) 5-ASA itself is absorbed from small intestine so pharmacokinetics / pharmaceutics matter Different formulations are used to overcome rapid absorption of 5- ASA from the proximal small intestine - Sulfasalazine (Azulfidine) - Mesalamine (Asacol, Pentasa, Lialda, Apriso, Delzicol) Balsalazide (Colazal) Olsalazine (Dipentum) -Rowasaenema, Canasa suppository

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15 Sulfasalazine (Azulfidine) Pro-drug combination of 5-ASA and sulfapyridine Is given orally, little amount is absorbed (10%) In the terminal ileum and colon, sulfasalazine is broken by azoreductase into: 5-ASA (not absorbed, active moiety) and Sulfapyridine (absorbed, side effects) Acetylator status matters with ADRs Idiosyncratic: SJS, TEN, DI Lupus, Hepatitis Dose dependent Crystalluria, Bone marrow depression, Megaloblastic anemia, Folic acid deficiency, Oligospermia

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17 Mesalamaine Compounds Compounds that contain 5-ASA and connected by the azo bond (N=N) to sulfapyridine moiety, another molecule of 5-ASA or to inert compound. - Sulfa free, well tolerated, have less side effects, and useful in patients sensitive or allergic to sulfa drugs Sulfasalazine: 5-ASA + sulfapyridine (Azulfidine) Olsalazine: 5-ASA + 5-ASA (Dipentum) Balsalazide: 5-ASA + inert carrier (Colazal) ph / extended release: Asacol, Lialda, Delzicol, Apriso Sustained release: Pentasa

18 5-ASA SITE OF RELEASE PER DESIGN OF VARIOUS DELIVERY SYSTEMS

19 SAFETY CONSIDERATIONS OF 5-ASA AGENTS Nephrotoxicity Nephrotoxicity rate 0.26% per patient year 1 Most often reported within the first 12 months of therapy 1 May be idiosyncratic rather than dose related 1 Caution recommended when used in patients with known (or history of) renal disease 2,3 FDA recommends monitoring BUN/serum creatinine Timely recognition of renal impairment and prompt discontinuation of 5 ASA in affected patients is important 1 Pregnancy / breastfeeding Safety in pregnancy demonstrated in several trials Milk: serum ratios considered acceptably low Considered safe for use in pregnancy and breastfeeding when indicated 1. Gisbert JP et al. Inflamm Bowel Dis. 2007;13: Asacol [prescribing information] Procter & Gamble Pharmaceuticals; Sep Lialda (delayed release mesalamine) [package insert]. Wayne, PA: Shire USA; Jan Kane S. Gastroenterol Clin N Am. 2003;32:323.

20 Glucocorticoids Prednisone, prednisolone (orally) Higher rate of absorption More adverse effects compared to rectal administration Hydrocortisone (enema or suppository): Less absorption rate than oral. Minimal side effects & Maximum tissue effects Induction of remission in moderate & severe active IBD Not used for maintaining remission Oral glucocorticoids is commonly used in active condition Rectal glucocorticoids are preferred in IBD involving rectum or sigmoid colon

21 Budesonide A potent synthetic compound given orally (controlled release tablets) to release drug in ileum and colon Low oral bioavailability (10%) Is subject to first pass metabolism Used in treatment of active forms of moderate to severe UC & Crohn s disease involving ileum and proximal colon Potency 15x that of prednisolone Delayed release capsule facilitates delivery to terminal ileum and proximal colon Efficacy comparable to prednisolone with fewer side effects in adults with ileocecal Crohns Multinational paediatric study completed 3 RCTs of oral budesonide 6mg/day, 3 mg/day and placebo Budesonide 6mg/day ineffective at preventing relapse over 12 months. RR relapse = 0.89 (95% CI: ) Similar results with 3mg/day

22 Immunomodulators Used to induce remission in IBD in active, severe conditions or steroid resistant patients. Immunomodulators include: Azathiporine, 6-mercatopurine Methotrexate Cyclosporine Tacrolimus

23 Purine Analogs Azathioprine & 6-mercaptopurine Azathioprine (Imuran) is a pro-drug of 6-mercaptopurine Inhibits purine synthesis Induction and maintenance of remission in IBD TPMT testing (thiopurine methyltransferase) -Homozygous deficiency (rare <1%) -Heterozygous deficiency (50% activity) Bone marrow depression: leukopenia, thrombocytopenia Gastrointestinal toxicity Pancreatitis Hepatic dysfunction CBC & liver enzymes are required in all patient

24 Azathioprine or 6-Mercaptopurine for inducing remission of Crohn s disease Sandborn W et al, Cochrane Review placebo controlled RCTs identified OR (95% CI) of response to AZA / 6-MP in active CD = 2.36 ( ), NNT = 5, OR (95% CI) for steroid sparing effect = 3.86 ( ), NNT = 3 OR (95% CI) for adverse event (allergy, leukopenia, pancreatitis, nausea) = 3.01 ( ), NNH = 14 Azathioprine & 6-MP are effective at inducing remission in active Crohn s disease.

25 Azathioprine for maintenance of remission in Crohns disease Pearson DC et al, Cochrane Review placebo controlled DBRCTs identified OR (95% CI) for maintenance of remission = 2.16 ( ), NNT = 7 Higher dose improved response (OR = 1.2 at 1mg/kg/day, 3.2 at 2mg/kg/day & 4.1 at 2.5mg/kg/day) OR for steroid sparing effect = 5.22 ( ), NNT = 3 OR for withdrawal due to adverse events = 4.36 ( )

26 LYMPHOMA & 6-MP/AZA 4 fold increased risk of lymphoma in IBD patients on IMD 1 Before putting the brakes on 6MP/AZA a closer look at the data reveals 2 : 1. Heterogeneity of the studies on the meta analysis 2. More severe IBD may raise the risk of lymphoma 3. Weigh Risk (if any) versus benefit 1.Kandiel A, Fraser AG, Korelitz Bl, et al. GUT 2005;54: McGovern DPB, Jewell DP. GUT 2005;

27 USE OF IMMUNOSUPPRESSANTS: HIGHER INCIDENCE OF ABNORMAL PAP SMEARS IN WOMEN WITH IBD Any abnormal pap Hx (%) High-grade lesions (%) Exposed to any immunosuppressant OR 3.1 ( ); p= Exposed Control p=0.01 exposed aza/6-mp Exposed Nonexposed Nonexposed Control Women >1 abnormal pap (%) Exposed to aza/6-mp OR 2.9 ( ); p= Exposed 22.0 Non-exposed Conclusions: Women with IBD carry a higher risk for clinically important cervical lesions than healthy controls The effect of immunomodulator use increases this risk Women with IBD are appropriate candidates for inclusion under ACOG guidelines for increased cancer screening Kane S, et al. DDW 2006, Los Angeles. Abstract #16

28 Methotrexate Folic acid antagonist - Inhibits dihydrofolate reductase required for folic acid activation Orally, S.C., I.M. Used to induce and maintain remission in inflammatory bowel diseases. Bone marrow depression Megaloblastic anemia

29 ANTI-TNF AGENTS Infliximab (Remicade) 1999 UC & CD Adalimumab (Humira) 2002 UC & CD Natalizumab (Tysabri) 2006 CD Certolizumab pegol (Cimzia) 2008 CD Golimumab (Simponi) 2009 UC Vetolizumab (Entyvio) 2014 UC & CD

30 INFLIXIMAB (REMICADE) Chimeric IgG monoclonal antibody to TNF-α infliximab is TNFα inhibitor It binds to TNFα, preventing it from activating TNF receptors Has an advantage that it is given SC and is approved for treatment of moderate to severe Crohn s disease, rheumatoid arthritis, psoriasis.

31 ADALIMUMAB (HUMIRA) Fully humanized IgG antibody to TNF-α Adalimumab is TNFα inhibitor It binds to TNFα, preventing it from activating TNF receptors Has an advantage that it is given SC and is approved for treatment of moderate to severe Crohn s disease, rheumatoid arthritis, psoriasis.

32 Anti-TNF Side effects Acute or early adverse infusion reactions - allergic reactions or anaphylaxis in 10% of patients Delayed infusion reaction - serum sickness-like reaction, 5% of patients Pretreatment with diphenhydramine, acetaminophen, corticosteroids is recommended Infection complications - Latent tuberculosis, sepsis, hepatitis B Loss of response to infliximab over time due to the development of antibodies Severe hepatic failure Rare risk of lymphoma

33 Rationale for Monitoring IBD Patients Treated with Anti-TNFs ~150,000 IBD patients are currently on anti-tnfs ~50% of IBD patients will require dose modification or switch to another treatment 1 Many patients with IBD who have symptoms may not have active inflammation Monitoring strategies that identify patients who have insufficient drug, anti-drug antibodies, or patients whose symptoms are due to causes other than active IBD may help guide treatment outcomes for individual patients 33 Alzafiri et al. Clinical and Experimental Gastroenterology 2011; (4):9-17 CONFIDENTIAL

34 The Role of anti-tnf Monitoring Tests in Clinical Practice 1. Knowing what factors are contributing to a patient s loss of response to a biologic may be helpful for determining an appropriate course of action 2. Empiric strategy may lead to intensification of treatment in patients: who are antibody positive and may have obtained a greater benefit by switching to another agent who have therapeutic levels of drug and no antibodies where TNF may not play a major role in the maintenance of inflammation who have symptoms that could be due to alternate etiologies CONFIDENTIAL 34

35 Detectable Serum Trough IFX Concentration is Associated with Higher Remission Rate and Endoscopic Improvement in UC Patients % of patients P<0.001 Study design: cohort study n=115 with moderate to severe UC Follow-up time: median 13.9 mo Efficacy Detectable serum IFX was associated with Higher remission rates (69% vs. 15%; P<0.001) Endoscopic improvement (76% vs. 28%; P<0.001) Undetectable serum IFX predicted an increased risk for colectomy (55% vs 7%; p<0.001) 35 Seow CH et al. Gut 2010;59:49-54 CONFIDENTIAL

36 Measuring Infliximab and ATI Concentrations In a retrospective analysis of 155 CD patients measuring IFX and ATI impacted treatment decisions in 73% of the clinical situations Detectable ATI Subtherapeutic IFX p< % 86% p< % 17% Subtherapuetic IFX concentration defined as =<12 mcg/ml at 4 wks or undetectable at trough Afif et al. Am J Gastroenterol. 2010; 105(5):

37 Published Treatment Algorithm in IBD: Patients With Loss of Response Positive ATI Negative ATI Consider change to another anti-tnf agent Therapeutic IFX concentration Subtherapeutic IFX concentration persistent disease Consider change to nonanti-tnf agent Active disease on endoscopy/radiology? yes Consider change to nonanti-tnf agent no Consider Investigating alternate etiologies Consider inc. infliximab dose or frequency Consider change to different anti-tnf agent active disease Consider change to different anti-tnf Consider change to nonanti-tnf agent 37 Afif W, et al. Am J Gastroenterol 2010;105: Yanai et al. Am J Gastroenterology 2010; 106: CONFIDENTIAL

38 Serum ADA and ATA Levels Correlate Well with Disease Activity N=66 IBD Patients (59 CD, 7 UC) with a cross-sectional study design Detectable ATA was associated with: ADA < 5µg/mL (p<0.001) Mucosal inflammation (p=0.03) Need for steroids (p=0.03) Previous IFX use (p=0.04) ADA concentration of < 5 µg/mlpredicted elevation in CRP in ATA negative samples Mean CRP levels were significantly higher in ATA+ vs. ATA- (12 vs. 2.1 mg/l, p=0.002) Yarur A. et al., DDW CONFIDENTIAL

39 CONSIDER THIS. Let the disease dictate therapy options Best options may not be possible cost& compliance concerns Disease education essential Weigh risks versus benefits, Top down therapy likely best If you do it, do it right! Testing & compliance

40 Thank you! Questions?